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A low maximal oxygen consumption (V̇o_2max) is a strong risk factor for premature mortality. Supervised endurance exercise training increases V̇o_2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts V̇o_2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous V̇o_2max response. Two independent preintervention RNA expression data sets were generated (n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in V̇o_2max (“predictor” genes). The HERITAGE Family Study (n = 473) was …